Mice were rendered tolerant to and physically dependent on morphine by daily subcutaneous (s.c.) injections of increasing doses of morphine for 3 weeks. The degree of tolerance was determined by measuring the increase in the median analgetic dose of morphine in relation to response to thermal stimulus, and dependence was determined by the precipitation of withdrawal jumping with the antagonist, naloxone. The concomitant daily administration of cycloheximide with morphine prevented the development of tolerance and physical dependence. The increase in brain serotonin turnover, which was noted to accompany development of tolerance and physical dependence, was also blocked. The findings suggest that the three responses to morphine may be closely related.
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Acknowledgements-This study was supported by grants from the National Institutes of Health, GMS-01839, the NAS-NRC Committee on Problems of Drug Dependence, and the Breon Fund of the School of Medicine.